3-keto-21-hydroxy-4, 9(11), 17(20)-pregnatriene and esters thereof



United States Patent 3-KETO-21-HYDROXY-4,9(11),17(20)-PREGNA- TRIENE AND ESTERS THEREOF John A. Hogg, Kalamazoo Township, Kalamazoo County, Philip F. Beal III, Portage Township, Kalamazoo County, and Frank H. Lincoln, Jr., Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application September 2, 1953, Serial No. 378,182

7 Claims. (Cl. 260-39745) The present invention relates to steroid compounds, and is more particularly concerned with the novel 21-oxygenated steroids, 3-keto-21-hydroxy-4,9( 1 1 17 (20 pregnatriene and 21-acylates thereof.

This application is a continuation-in-part of our copending applications Serial Number 307,385, filed August 30, 1952, and Serial Number 345,677, filed March 30, 1953.

The novel compounds of the present invention may be represented by the formula:

CHzOR H CH;

and 21-acylates thereof, compounds which are useful and interesting intermediates in the synthesis of other steroid compounds, and, if desired, can be converted to physiologically active compounds. For example, 3-ket0-21-hydroxy 4,9(11),17(20) pregnatriene 21 acetate on treatment with osmium tetroxide and hydrogen peroxide produces 3,20 diketo 17a,21 dihydroxy 4,9(l1)- pregnadiene 21-acetate, which on bromination and oxidation with N-bromoacetamide and perchloric acid gives 9a bromo 17a hydroxy corticosterone 21 acetate, from which cortisone acetate is obtained by further oxidation with chromic acid followed by debromination with zinc. Other objects and uses of the present invention Will be apparent to one skilled in the art to which this invention pertains.

The novel 3 keto 21 hydroxy 4,9(11),17(20)- pregnatriene is prepared by dehydration of 3-keto-ll,8,21- dihydroxy-4,17(20)-pregnadiene, by concomitant hydrolysis and dehydration of a 3-keto-11[3,21-dihydroxy- 5,17(20)-pregnadiene 3-ketal, or by concomitant hydrolysis and dehydration of a 3-keto-11fi,21-dihydroxy- 5,l7(20)-pregnadiene 3-ketal 11-bimeta1lic-hydridecomplex such as that obtained by reduction of a 3-ketal of 3,1l-diketo-S,17(20)-pregnadiene-21-oid acid 21-ester with lithium aluminum hydride. The nature of the 3- ketal group or 21-ester group, if present in the starting steroid, is not critical. According to the process of the present invention, the starting steroid, dissolved in a water-immiscible organic solvent to provide a waterimmiscible phase of a liquid-liquid two-phase system, is reacted with a water-miscible strong acid, dissolved in an aqueous solvent to provide the aqueous phase of the liquid-liquid two-phase system, by mixing the two phases at a temperature below about 200 degrees centigrade. After completion of the reaction, the 3-keto-2l-hydroxy- 4,9(l1),17(20)-pregnatriene product can be isolated from the reaction mixture, for example, by evaporating the solvents from the separated organic phase. The crude product can be purified, if desired, by recrystallization, chromatographic adsorption methods, etc. The 21-acylates of 3-keto-21-hydroxy-4,9(1l),17(20)-pregnatriene can be prepared by esterification of the parent hydroxysteroid with an acylating agent such as, for example, an acid, acid anhydride, acid halide, ester of an acid with a lower alcohol, ketene, etc., as more fully described in Examples 2 through 6.

The following examples are illustrative of the products and processes of the present invention, but are not to be construed as limiting.

Example 1.3 keto 21 hydroxy 4,9(11),I7(20)- pregnatriene and its ZI-acylates The methyl ester of 3,11-diketo-4,l7(20)-pregnadien- 21-oic acid B-ethylene-glycol ketal (1.03 grams) is dissolved in 25 milliliters of benzene, and absolute ethyl ether (35 milliliters) is added. The resulting solution is added dropwise, with stirring, to one gram of lithium aluminum hydride in fifty milliliters of absolute ethyl ether. After the addition is complete, the resulting mixture is heated under reflux for about one hour. Fifty milliliters of a solution containing 25 milliliters of concentrated hydrochloric acid and 25 milliliters of water is then added dropwise, the stirring being continued. The heterogeneous mixture is then heated under reflux for one hour with vigorous stirring. After cooling, the organic layer is separated, the water layer extracted several times with ether, and the organic layer and ether extracts combined. The ether and suflicient benzene to dry the remaining solution is then distilled. The dry benzene solution is chromatographed on a synthetic magnesium silicate (Florisil) column, ten percent acetone in normal-hexane (Skellysoive B) being used for elution. The 3 keto 21 a hydroxy 4,9(11),17(20) pregnatriene obtained weighs 0.633 grain. An analytically pure sample, obtained by recrystallization from acetone, melted at 142 to 143 degrees centigrade; [041 plus 154 degrees centigrade (in acetone).

Analysis-Calculated for C21H2802I C, 80.73; H, 9.02. Found: C, 80.90; H, 9.08.

Example 2.3 keto 21 hydroxy 4,9(11),17(20)- pregnatriene 21 -acetate 3 keto 21 hydroxy 4,9(11),l7(20) pregnatriene 21-acetate is obtained by treating 3-keto-21-hydroxy 4,9(11),17(20)-pregnatriene with acetic anhydride in the presence of pyridine using the general esterification procedure of Shriner and Fuson [The Systematic Identification of Organic Compounds, John Wiley and Sons, Inc., New York, Third edition, 1948, page The structure of the product was confirmed by infra-red light absorption analysis; melting point 107 to 108 degrees centigrade.

Example 3.3 keto i- 21 hydroxy 4,9(11),17(20)- pregrzatriene 21 -benz0ate The 21 benzoate of 3 keto 21 hydroxy- 4,9(1l),17(20)-pregnatriene is obtained by treating the 2l-hydroxysteroid with benzoyl chloride and pyridine following the esterification procedure of Shriner and Fuson [The Systematic identification of Organic Compounds, John Wiley and Sons, Inc., New York, Third edition, 1948,.page 164].

Example 4.3 keto 2] hydroxy 4,9(1I),17(20)- pregnatriene 21 -pr0pionate Following the procedure of Example 2, the 21-propionate of 3-keto-2l-hydroxy4,9( l1),l7(20)-pregnatriene is prepared by reaction of propionic anhydride with 3-keto-21-hydroxy-4,9( 1 1),17 (20) -pregnatriene.

Example 5.3 keto 21 hydroxy 4,9(11),17(20)- pregnatriene 21-(fl-cyclopentylpropionate) The 21-(B-cyclopentylpropionate) of 3-keto-21-hydr0xy-4,9(11),17(20)-pregnatriene is obtained by reaction of the free 21-hydroxy compound with fl-cyclopentyl- .propionyl chloride, according to the procedure of Example 3.

Example 6.3 keto 21 hydroxy 4,9(I1),17(20)- pregnatriene 21 phenylncetate Following the method of Example 3, reaction of phenylaeetyl chloride with 3-keto-21hydroxy-4,9(11), l7(20)-pregnatriene is productive of 3-keto-2l-hydroxy- 4,9(1 1),l7(20)-pregnatriene 2l-phenylacetate.

1n the same manner as shown in Examples 2 through art, and the invention is therefore limited only by the scope of the appended claims.

We claim: 1. A 3 keto 21 oxygenated 4,9(11),17(20)- 5 pregnatriene of the formula:

'CHa

CH2-OR H OH: I

wherein OR is selected from the group consisting of hydroxy and acylox-y of the formula AcO, Ac being the acyl radical of a hydrocarbon carboxylic acid containing from one to-eight carbon atoms, inclusive.

2. 3 keto 21 hydroxy 4,9(11),1'7(20)-pregnatriene.

3. A 3 keto 21 hydroxy 4,9(11),17(20)pregnatriene 2l-acylate wherein the aeylate radical is of the formula AcO, Ac being the acyl radical of a hydrocarbon carboxylic acid containing from one to eight carbon atoms, inclusive.

4. 3 keto 21 hydroxy 4,9(l1),17(20) pregnatriene ZI-acetate.

5. 3 keto 21 hydroxy 4,9(l1),17(20) pregnatriene 21-propionate.

6. 3 keto 21 hydroxy 4,9(11),17(20) pregnatriene 2l-(p-cyclopentylpropionate).

7. 3 keto 21 hydroxy 4,9(11),l7(20) pregnatriene 21-phenylacetatc.

No references cited. 

1. A 3 - KETO - 21 - OXYGENATED - 4,9(11),17(20)PREGNATRIENE OF THE FORMULA: 